The invention relates to novel coumarin derivatives, to processes for preparing them, and to their use as medicinal products which can inhibit serine proteases and cysteine proteases.
The invention applies more particularly to serine or cysteine proteases, such as leukocyte elastase, thrombin, clotting factors (for example IXa, Xa, XIa, XIIa and VIIa), complement factors, plasmin, plasminogen activators (u-PA and t-PA), cathepsin G, acrosin, chymases, tryptases, chymotrypsin, trypsin and cathepsin B.
More specifically, the invention relates to novel coumarin derivatives which can act selectively on a given protease.
Serine protease and cysteine protease are involved in a great many physiological processes. Pathological states can become established when a disequilibrium is observed between the protease and its natural macromolecular inhibitor(s). Low-molecular-weight synthetic inhibitors can be used in this case to counteract excess proteolysis and can thus be of great therapeutic value in the following pathologies: pulmonary emphysema, rheumatoid arthritis, ageing of the skin and inflammation (involvement of leukocyte elastase and cathepsin G); pancreatitis (involvement of pancreatic elastase, chymotrypsin and trypsin): tumor invasion and metastasis (plasmin, plasminogen activators and cathepsin B); thrombosis, cerebral and coronary infarction (involvement of thrombin and clotting factors); thrombolysis and fertility disorders (plasmin and plasminogen activators); attacks by parasites and viruses (some of these organisms produce serine and cysteine proteases).
Among the serine protease inhibitors described in the literature and obtained by total synthesis, modified peptides or compounds of totally non-peptide nature are distinguished (Demuth 1990,J. Enzym. Inhib. 3:249-278; Bernstein et al. 1994, in Progress in Medicinal Chemistry 31: 59-120). These inhibitors have the advantage of being potentially more stable with respect to in vivo metabolization processes and of optionally being able to be administered orally.
Many classes of synthetic non-peptide compounds which have serine protease inhibitory properties are known from the prior art. Among these, suicide substrates have been prepared, such as haloenol and ynenol lactones (Daniels et al. 1983, J. Biol Chem. 258: 15046-15053;Katzenellenbogen et al. 1992, Bioorg. Med. Chem. Lett. 2: 1399-1404; Tam et al. 1984, J. Am. Chem. Soc. 106: 6849-6851), isocoumarins (Harper et al. 1985, Biochemistry 24: 1831-1841; Harper 1985, Biochemistry 24: 7200-7213), 3,4-dihydro-6-halomethylcoumarins (Bxc3xa9chet et al. 1973, Eur. J. Biochem. 35: 527-539; Mor et al. 1990 Biochim. Biophys. Acta 1038: 119-124), functionalized arylcyclopeptides (Reboud-Ravaux et al. 1991, Boichem. Biophys. Res. Commun. 178: 352-359; Wakselman et al. 1993, J. Med. Chem. 36: 1539-1547) and xcex2-lactams (Doherty et al. 1986, Nature 322:192-194; Knight et al. 1992, Biochemistry 31: 8160-8170; Maillard et al. 1990, Eur. J. Biol. 52: 213-221; Wakselman et al. 1991, FEBS Lett. 282: 377-381).
Among these inhibitors of suicide substrate type, halomethyldihydrocoumarins have attracted particular attention. They have shown good inhibitory activity with respect to a large number of serine proteases, in particular including xcex1-chymotrypsin, pig pancreatic elastase, human leukocyte elastase, urokinase and thrombin (Bxc3xa9chet et al. 1973, Eur. J. Biochem. 35: 527-539; Bxc3xa9chet et al. 1977, Biochimie 59: 231-239; Bxc3xa9chet et al. 1973, Biochimie 59: 241-246; Vilain et al. 1991, Biochim. Biophys. Acta 1076: 401-405; Reboud-Ravaux et al. 1990, Biochim. Biophys. Acta 1038: 119-124). However, these products, which are difficult to synthesize, lack selectivity.
It is of the greatest interest to synthesize protease inhibitors which are specific for a given protease, in order to inhibit this enzyme without acting on nearby proteases.
The present invention relates to the preparation of novel coumarin derivatives which allow this aim to be achieved since they combine activity and specificity.
The invention also relates to the preparation of novel coumarin derivatives whose synthesis is more readily accessible.
The invention relates to compounds corresponding to the general formula (I) below: 
in which:
X, Xxe2x80x2 and Xxe2x80x3, independently of each other, represent O or S,
Y represents O, S, NH or NHS,
R3 represents
a cycloalkyl group, in particular of 3 to 12 carbon atoms and optionally containing at least one hetero atom chosen from O, S and N, optionally substituted by one or more linear or branched alkyl group(s) of 1 to 6 carbon atoms,
an aryl group, in particular a phenyl or naphthyl group optionally substituted by 1 to 7 and in particular 1 to 5 substituents chosen from: a halogen atom; a linear or branched alkyl group of 1 to 6 carbon atoms; a linear or branched alkoxy group of 1 to 6 carbon atoms; a linear or branched alkylthio group of 1 to 6 carbon atoms; an amino group optionally substituted by 1 or 2 linear or branched hydrocarbon-based chain(s) of 1 to 6 carbon atoms; a linear or branched acylamino group of 1 to 6 carbon atoms; a perhaloalkyl group of 1 or 2 carbon atoms, in particular xe2x80x94CF3; a hydroxyl group; a mercapto; a nitro group; a cyano group; a carboxylic or carboxamide radical; a linear or branched alkoxycarbonyl group of 1 to 6 carbon atoms; a carbaldehyde group; a sulfonamide group optionally mono- or disubstituted on the nitrogen with 1 or 2 linear or branched hydrocarbon-based chain(s) of 1 to 6 carbon atoms; an amidine or guanidine group;
a 5- to 14-membered, in particular 5- or 6-membered, mono- or polycyclic heteroaryl group containing one or more nitrogen and/or sulfur and/or oxygen atoms, in particular a pyridyl group, optionally substituted by 1 to 6 substituents chosen from: a halogen atom; a linear or branched alkyl group of 1 to 6 carbon atoms; an aryl group; a linear or branched alkoxy group of 1 to 6 carbon atoms; a linear or branched alkylthio group of 1 to 6 carbon atoms; an amino group optionally substituted by 1 or 2 linear or branched hydrocarbon-based chain(s) of 1 to 6 carbon atoms; a linear or branched acylamino group of 1 to 6 carbon atoms; a perhaloalkyl group of 1 or 2 carbon atoms, in particular xe2x80x94CF3; a hydroxyl group; a mercapto group; a nitro group; a cyano group; a carboxylic or carboxamide radical; a linear or branched alkoxycarbonyl group of 1 to 6 carbon atoms; a carbaldehyde group; a sulfonamide group optionally mono- or disubstituted on the nitrogen with 1 or 2 linear or branched hydrocarbon-based chain(s) of 1 to 6 carbon atoms; an amidine or guanidine group,
with the proviso that R3 is other than a cycloalkyl group or an aryl group when Y represents NH;
R3 advantageously representing xe2x80x94C6H5, xe2x80x94C6H4CH3, xe2x80x94C6H4I, xe2x80x94C6H4NO2, xe2x80x94C6H4F, xe2x80x94C6H4Br, xe2x80x94C6H4Cl, xe2x80x94C6H4CF3, xe2x80x94C6H4OCH3, xe2x80x94C6H3Cl2, xe2x80x94C6H3ClCH3, xe2x80x94C6H3ClOCH3, 
R5, R6, R7 and R8, which may be identical or different, represent hydrogen; a halogen atom; a linear or branched alkyl group of 1 to 6 carbon atoms; a linear or branched haloalkyl group of 1 to 6 carbon atoms, in particular halomethyl and in particular xe2x80x94CH2Cl; a perhaloalkyl group of 1 or 2 carbon atoms, in particular xe2x80x94CF3; a linear or branched alkyl group of 1 to 6 carbon atoms bearing an amine, amidine or guanidine function or a sulfonium function bearing two linear or branched alkyl substituents of 1 to 6 carbon atoms, an aryl or aralkyl group in which the alkyl group contains from 1 to 6 carbon atoms; a carboxylic or carboxamide radical; a linear or branched alkoxycarbonyl group of 1 to 6 carbon atoms; a linear or branched alkoxy group of 1 to 6 carbon atoms; a linear or branched alkylthio group of 1 to 6 carbon atoms; an aralkyl group in which the linear or branched alkyl radical contains from 1 to 6 carbon atoms; an aryl group optionally substituted by one or more groups chosen from halogen, linear or branched alkyl of 1 to 6 carbon atoms or linear or branched alkoxy of 1 to 6 carbon atoms; an amino group optionally substituted by 1 or 2 linear or branched hydrocarbon-based chain(s) of 1 to 6 carbon atoms; a linear or branched acylamino group of 1 to 6 carbon atoms; a hydroxyl group; a mercapto group; a nitro group; a cyano group; a sulfonamide group optionally mono- or disubstituted on the nitrogen with 1 or 2 linear or branched hydrocarbon-based chain(s) of 1 to 6 carbon atoms; an amidine or guanidine group; a group xe2x80x94CH2xe2x80x94Oxe2x80x94 R9,
in which R9 represents:
hydrogen;
a linear or branched alkyl group of 1 to 6 carbon atoms; aryl, in particular phenyl or naphthyl optionally substituted by one or more groups chosen from halogen, linear or branched alkyl of 1 to 6 carbon atoms or linear or branched alkoxy of 1 to 6 carbon atoms; arylalkyl of 1 to 6 carbon atoms; R11C(xe2x95x90O)xe2x80x94, in which R11 represents a linear or branched alkyl group of 1 to 6 carbon atoms, optionally mono- or polyhalogenated, and in particular xe2x80x94CF3;
a group xe2x80x94CH2xe2x80x94Sxe2x80x94R9, in which R9 has the meaning given above;
a group xe2x80x94CH2NR12R13, in which R12 and R13, which may be identical or different, have the meanings given above with regard to R9;
R5, R6, R7 and R8 advantageously representing Hxe2x80x94, ClCH2xe2x80x94, CH3C(xe2x95x90O)xe2x80x94Oxe2x80x94CH2xe2x80x94, C2H5xe2x80x94C(xe2x95x90O)xe2x80x94Oxe2x80x94CH2xe2x80x94, (CH3)3Cxe2x80x94C(xe2x95x90O)xe2x80x94Oxe2x80x94CH2xe2x80x94, (CH3)2CHxe2x80x94C(xe2x95x90O)xe2x80x94Oxe2x80x94CH2xe2x80x94, CH3(CH2)2xe2x80x94C(xe2x95x90O)xe2x80x94Oxe2x80x94CH2xe2x80x94, CF3xe2x80x94C(xe2x95x90O)xe2x80x94Oxe2x80x94CH2, C6H5xe2x80x94Sxe2x80x94CH2xe2x80x94, NH2xe2x80x94CH2xe2x80x94, Br and the salts of organic or inorganic acids or of organic or inorganic bases and the optical isomers of the compounds of formula (I); with the proviso that the following products are excluded: 
R3 representing C6H5, R6 representing H or CH3,
with the proviso also that:
2) when, in the general formula, X, Xxe2x80x2, Xxe2x80x3 and Y represent O and R6 represents xe2x80x94CH2Cl, R3 is other than xe2x80x94C6H5, xe2x80x94C6H4CH3, xe2x80x94C6H4Cl, xe2x80x94C6H4I, xe2x80x94C6H4mNO2, xe2x80x94C6H3pClmCH3, xe2x80x94C6H4mBr, xe2x80x94C6H4mF, xe2x80x94C6H4mOCH3, 
3) when, in the general formula, X, Xxe2x80x2, Xxe2x80x3 and Y represent O, and R3 represents xe2x80x94C6H4pCHO, R7 is other than an alkoxy substituent of 1 to 6 carbon atoms,
4) when, in the general formula, X, Xxe2x80x2, Xxe2x80x3 and Y represent O and R6 represents xe2x80x94C6H5,
(xe2x88x92) R3 is other than xe2x80x94H, xe2x80x94CH3, xe2x80x94NO2, xe2x80x94Cl or xe2x80x94Br when R5, R7 and R8 represent xe2x80x94H,
(xe2x88x92) R7 is other than xe2x80x94Br or xe2x80x94N(CH2CH3)2, when R5, R6 and R8 represent xe2x80x94H,
(xe2x88x92) R8 is other than xe2x80x94OCH3 or xe2x80x94NO2 when R5, R6 and R7 represent xe2x80x94H,
5) when, in the general formula, X, Xxe2x80x2, Xxe2x80x3 and Y represent O and R5, R6, R7 and R8 represent xe2x80x94H, R3 is other than 
with the proviso also that:
6) when, in the general formula, X, Xxe2x80x2 and Xxe2x80x3 represent O, Y represents NH and R3 represents 2-thiazolyl, R6 and R8 are other than xe2x80x94H, xe2x80x94NO2, xe2x80x94Br, xe2x80x94Cl or xe2x80x94I,
7) when, in the general formula, X, Xxe2x80x2 and Xxe2x80x3 represent O, Y represents NH and xe2x80x94R3 represents 2-pyridyl,
(xe2x88x92) R6 is other than xe2x80x94NO2, xe2x80x94NH2 or xe2x80x94NHCOCH3 when R5, R7 and R8 represent xe2x80x94H,
(xe2x88x92) R7 is other than xe2x80x94NO2 or xe2x80x94NH2 when R8 represents xe2x80x94H, xe2x80x94OH or xe2x80x94OCH3, and R5 and R6 represent H,
8) when, in the general formula, X, Xxe2x80x2 and Xxe2x80x3 represent O, Y represents NH and R5, R6, R7 and R8 represent xe2x80x94H, R3 is other than: 
9) and with the proviso that the following products are excluded: 
Salts which are preferred according to the invention are physiologically acceptable salts.
By way of example, and in a non-exhaustive manner, mention may be made of the salts of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, toluenesulfonic acid, lactic acid, citric acid, tartaric acid, succinic acid and salts of inorganic bases such as sodium hydroxide, potassium hydroxide, aqueous ammonia and organic bases such as triethylamine and L-lysine.
The invention also relates to compounds corresponding to the following formula: 
in which R3, X and Y have the meanings given above, R and Rxe2x80x2 have the same meanings as R5, R6, R7 and R8 as defined above, and in particular R and Rxe2x80x2 correspond to R6 and R8 respectively.
The invention also relates to compounds corresponding to the following formula: 
in which
R3 represents
an aryl group, in particular phenyl or naphthyl, optionally substituted by 1 to 7, in particular 1 to 5, substituents chosen from: a halogen atom; a linear or branched alkyl group of 1 to 6 carbon atoms; a linear or branched alkoxy group of 1 to 6 carbon atoms; a linear or branched alkylthio group of 1 to 6 carbon atoms; an amino group optionally substituted by 1 or 2 linear or branched hydrocarbon-based chain(s) of 1 to 6 carbon atoms; a linear or branched acylamino group of 1 to 6 carbon atoms; a perhaloalkyl group of 1 or 2 carbon atoms, in particular xe2x80x94CF3; a hydroxyl group; a mercapto group; a nitro group; a cyano group; a carboxylic or carboxamide radical; a linear or branched alkoxycarbonyl group of 1 to 6 carbon atoms; a carbaldehyde group; a sulfonamide group optionally mono- or disubstituted on the nitrogen with 1 or 2 linear or branched hydrocarbon-based chain(s) of 1 to 6 carbon atoms; an amidine or guanidine group;
a 5- to 14-membered, in particular 5- or 6-membered, mono- or polycyclic heteroaryl group containing one or more nitrogen and/or sulfur and/or oxygen atoms, in particular a pyridyl group, optionally substituted by 1 to 6 substituents chosen from: a halogen atom; a linear or branched alkyl group of 1 to 6 carbon atoms; an aryl group; a linear or branched alkoxy group of 1 to 6 carbon atoms; a linear or branched alkylthio group of 1 to 6 carbon atoms; an amino group optionally substituted by 1 or 2 linear or branched hydrocarbon-based chain(s) of 1 to 6 carbon atoms; a linear or branched acylamino group of 1 to 6 carbon atoms; a perhaloalkyl group of 1 or 2 carbon atoms, in particular xe2x80x94CF3; a hydroxyl group; a mercapto group; a nitro group; a cyano group; a carboxylic or carboxamide radical; a linear or branched alkoxycarbonyl group of 1 to 6 carbon atoms; a carbaldehyde group; a sulfonamide group optionally mono- or disubstituted on the nitrogen with 1 or 2 linear or branched hydrocarbon-based chain(s) of 1 to 6 carbon atoms; an amidine or guanidine group,
with the proviso that R3 is other than an aryl group when Y represents NH;
R6 and Y have the meanings given above.
The invention also relates to compounds corresponding to the following formula: 
R3 and Y have the meaning given above and R6 has the meaning given above with the exception of ClCH2xe2x80x94.
These compounds are advantageous in the context of their use on pathologies involving elastase.
The invention also relates to compounds corresponding to the following formula: 
in which
R6 represents H or CH3,
R3 represents mClC6H4, 
The invention also relates to compounds corresponding to the following formula: 
in which R6 represents ClCH2xe2x80x94 and R3 is chosen from 
The invention also relates to compounds corresponding to the following formula: 
in which R9 represents 
and R3 is chosen from 
or R9 represents 
and R3 is chosen from 
or R9 represents 
and R3 represents 
or R9 represents 
and R3 represents 
or R9 represents 
and R3 represents 
The invention also relates to compounds corresponding to the formula 
in which R12xe2x95x90R13xe2x95x90H and R3 represents 
The invention also relates to compounds corresponding to the formula: 
in which R3 represents 
The invention also relates to compounds corresponding to the following formula: 
in which R3 is chosen from: 
The invention also relates to compounds corresponding to one of the following formulae: 
The invention also relates to compounds corresponding to the following formula: 
in which:
R11=CH3xe2x80x94, C2H5xe2x80x94, C3H7xe2x80x94, (CH3)3Cxe2x80x94, (CH3)2CHxe2x80x94 or to the following formula: 
xe2x80x83or to the following formula: 
xe2x80x83in which R3 represents ethyl and R9 represents phenyl.
The invention also relates to a pharmaceutical composition, characterized in that it comprises, as active substances, at least one of the compounds described above, in combination with a pharmaceutically acceptable vehicle.
The invention also relates to a cosmetic composition, characterized in that it comprises, as active substances, at least one of the compounds described above.
The invention also relates to the use of one of the compounds described above for the preparation of a medicinal product intended for treating pathologies involving serine proteases such as thrombin, chymotrypsin, elastases, cathepsin G, plasminogen activators (u-PA and t-PA), plasmin, tryptases, chymases, cysteine proteases, clotting factors, complement factors, acrosin or kallicrein.
The invention also relates to the use of one of the compounds of the general formula below: 
in which:
X, Xxe2x80x2 and Xxe2x80x3, independently of each other, represent O or S,
Y represents O, S, NH or NHS,
R3 represents p2 a cycloalkyl group, in particular of 3 to 12 carbon atoms and optionally containing at least one hetero atom chosen from O, S and N, optionally substituted by one or more linear or branched alkyl group(s) of 1 to 6 carbon atoms,
an aryl group, in particular a phenyl or naphthyl group optionally substituted by 1 to 7 and in particular 1 to 5 substituents chosen from: a halogen atom; a linear or branched alkyl group of 1 to 6 carbon atoms; a linear or branched alkoxy group of 1 to 6 carbon atoms; a linear or branched alkylthio group of 1 to 6 carbon atoms; an amino group optionally substituted by 1 or 2 linear or branched hydrocarbon-based chain(s) of 1 to 6 carbon atoms; a linear or branched acylamino group of 1 to 6 carbon atoms; a perhaloalkyl group of 1 or 2 carbon atoms, in particular xe2x80x94CF3; a hydroxyl group; a mercapto; a nitro group; a cyano group; a carboxylic or carboxamide radical; a linear or branched alkoxycarbonyl group of 1 to 6 carbon atoms; a carbaldehyde group; a sulfonamide group optionally mono- or disubstituted on the nitrogen with 1 or 2 linear or branched hydrocarbon-based chain(s) of 1 to 6 carbon atoms; an amidine or guanidine group;
a 5- to 14-membered, in particular 5- or 6-membered, mono- or polycyclic heteroaryl group containing one or more nitrogen and/or sulfur and/or oxygen atoms, in particular a pyridyl group, optionally substituted by 1 to 6 substituents chosen from: a halogen atom; a linear or branched alkyl group of 1 to 6 carbon atoms; an aryl group; a linear or branched alkoxy group of 1 to 6 carbon atoms; a linear or branched alkylthio group of 1 to 6 carbon atoms; an amino group optionally substituted by 1 or 2 linear or branched hydrocarbon-based chain(s) of 1 to 6 carbon atoms; a linear or branched acylamino group of 1 to 6 carbon atoms; a perhaloalkyl group of 1 or 2 carbon atoms, in particular xe2x80x94CF3; a hydroxyl group; a mercapto group; a nitro group; a cyano group; a carboxylic or carboxamide radical, a linear or branched alkoxycarbonyl group of 1 to 6 carbon atoms; a carbaldehyde group; a sulfonamide group optionally mono- or disubstituted on the nitrogen with 1 or 2 linear or branched hydrocarbon-based chain(s) of 1 to 6 carbon atoms; an amidine or guanidine group,
R3 advantageously representing xe2x80x94C6H5, xe2x80x94C6H4CH3, xe2x80x94C6H4I, xe2x80x94C6H4NO2, xe2x80x94C6H4F, xe2x80x94C6H4Br, xe2x80x94C6H4Cl, xe2x80x94C6H4CF3, xe2x80x94C6H4OCH3, xe2x80x94C6H3Cl2, xe2x80x94C6H3ClCH3, xe2x80x94C6H3ClOCH3, 
R5, R6, R7 and R8, which may be identical or different, represent hydrogen; a halogen atom; a linear or branched alkyl group of 1 to 6 carbon atoms; a linear or branched haloalkyl group of 1 to 6 carbon atoms, in particular halomethyl and in particular xe2x80x94CH2Cl; a perhaloalkyl group of 1 or 2 carbon atoms, in particular xe2x80x94CF3; a linear or branched alkyl group of 1 to 6 carbon atoms bearing an amine, amidine or guanidine function or a sulfonium function bearing two linear or branched alkyl substituents of 1 to 6 carbon atoms, an aryl or aralkyl group in which the alkyl group contains from 1 to 6 carbon atoms; a carboxylic or carboxamide radical; a linear or branched alkoxycarbonyl group of 1 to 6 carbon atoms; a linear or branched alkoxy group of 1 to 6 carbon atoms; a linear or branched alkylthio group of 1 to 6 carbon atoms; an aralkyl group in which the linear or branched alkyl radical contains from 1 to 6 carbon atoms; an aryl group optionally substituted by one or more groups chosen from halogen, linear or branched alkyl of 1 to 6 carbon atoms or linear or branched alkoxy of 1 to 6 carbon atoms; an amino group optionally substituted by 1 or 2 linear or branched hydrocarbon-based chain(s) of 1 to 6 carbon atoms; a linear or branched acylamino group of 1 to 6 carbon atoms; a hydroxyl group; a mercapto group; a nitro group; a cyano group; a sulfonamide group optionally mono- or disubstituted on the nitrogen with 1 or 2 linear or branched hydrocarbon-based chain(s) of 1 to 6 carbon atoms; an amidine or guanidine group; a group xe2x80x94CH2xe2x80x94Oxe2x80x94R9,
in which R9 represents:
hydrogen;
a linear or branched alkyl group of 1 to 6 carbon atoms; aryl, in particular phenyl or naphthyl. optionally substituted by one or more groups chosen from halogen, linear or branched alkyl of 1 to 6 carbon atoms or linear or branched alkoxy of 1 to 6 carbon atoms; arylalkyl of 1 to 6 carbon atoms; R11C(xe2x95x90O)xe2x80x94, in which R11 represents a linear or branched alkyl group of 1 to 6 carbon atoms, optionally mono- or polyhalogenated, and in particular xe2x80x94CF3;
a group xe2x80x94CH2xe2x80x94Sxe2x80x94R9, in which R9 has the meaning given above;
a group xe2x80x94CH2NR12R13, in which R12 and R13, which may be identical or different, have the meanings given above with regard to R9;
R5, R6, R7 and R8 advantageously representing Hxe2x80x94, ClCH2xe2x80x94, CH3C(xe2x95x90O)xe2x80x94Oxe2x80x94CH2, C2H5xe2x80x94C(xe2x95x90O)xe2x80x94Oxe2x80x94CH2xe2x80x94, (CH3)3Cxe2x80x94C(xe2x95x90O)xe2x80x94Oxe2x80x94CH2xe2x80x94, (CH3)2CHxe2x80x94C(xe2x95x90O)xe2x80x94Oxe2x80x94CH2xe2x80x94, CH3(CH2)2xe2x80x94C(xe2x95x90O)xe2x80x94Oxe2x80x94CH2xe2x80x94, CF3xe2x80x94C(xe2x95x90O)xe2x80x94Oxe2x80x94CH2, C6H5xe2x80x94Sxe2x80x94CH2xe2x80x94, NH2xe2x80x94CH2xe2x80x94, Br and the salts of organic or inorganic acids or of organic or inorganic bases
and the optical isomers of the compounds of formula (I);
for the preparation of a medicinal product intended for treating pathologies involving thrombin, cathepsin G, plasminogen activators, plasmin, tryptase, chymase or cysteine proteases.
The invention also relates to the use of a compound of formula: 
in which R3 represents an aryl group substituted by one or more halogens, NO2, an alkyl radical of 1 to 6 carbon atoms or an alkoxy radical of 1 to 6 carbon atoms,
for the preparation of a medicinal product intended for treating pathologies involving thrombin.
The processes described below can be used to prepare the compounds of the invention.
A general method for synthesizing esters, thioesters, amides and N-[aryl/alkyl]sulfanylamides of substituted 2-oxo-2H-1-benzopyran-3-carboxylic acids is as follows.
The ethyl esters of 2-oxo-2H-1-benzopyran-3-carboxylic acids can be obtained from the appropriate salicylaldehyde following the methods described in L. Pochet et al., J. Med. Chem. 1996, 39: 2579-2585 and in the examples of the present patent application (see later).
This synthesis can be illustrated by the following reaction scheme: 
Rxe2x80x2=ORxe2x80x3, SRxe2x80x3, NHRxe2x80x3, NHSRxe2x80x3
in which Rxe2x80x3 represents R3 defined above and R represents R5, R6, R7 and/or R8 described above,
(i) ethyl malonate; (ii) HCl/H2O/EtOH; (iii) SOCl2; (iv) Rxe2x80x3OH or Rxe2x80x3SH or Rxe2x80x3NH2 or Rxe2x80x3SNH2/pyridine/dioxane
One method for synthesizing esters, thioesters and amides of substituted 2-oxo-2H-1-benzothiopyran-3-carboxylic acids is as follows.
The ethyl esters of 2-oxo-2H-1-benzothiopyran-3-carboxylic acids can be prepared according to the method described in O. Meth Cohn and Tarnowski B., Synthesis, 1978, 1: 56-58 (ixe2x86x92iii below). The subsequent steps are based on the methods described in L. Pochet et al., J. Med. Chem. 1996, 39: 2579-2585, and in the examples of the present patent application (ivxe2x86x92vi below).
This synthesis can be illustrated by the reaction scheme below: 
in which Rxe2x80x3 represents R3 defined above and R represents R5, R6, R7 and/or R8 described above,
(i) t-C4H9SH/DMF; (ii) ethyl cyanoacetate; (iii) polyphosphoric acid; (iv) HCl/H2O/EtOH; (v) SOCl2; (vi) Rxe2x80x3OH or Rxe2x80x3SH or Rxe2x80x3NH2/pyridine/dioxane.
One method for synthesizing esters, thioesters and amides of substituted 2-oxo-2H-1-benzopyran-3-carbothioic acids is as follows.
The o-ethyl esters of 2-oxo-2H-1-benzopyran-3-carbothioic acids can be prepared according to the method described in B. S. Kirkiacharian and A. Danan, Synthesis, 1986, 5: 383-5 and in G. Barnikow and Stickmann G., Chem. Ber., 1967, 100: 1428-1435 (step i). The subsequent steps are based on the methods described in L. Pochet et al., J. Med. Chem. 1996, 39: 2579-2585 and in the examples of the present patent application.
This synthesis can be illustrated by the reaction scheme below: 
in which Rxe2x80x2 represents R3 defined above and R represents R5, R6, R7 and/or R8 described above,
(i) ethyl monothiomalonate; (ii) HCl/H2O/EtOH; (iii) SOCl2; (iv) Rxe2x80x3OH or Rxe2x80x3SH or Rxe2x80x3NH2/pyridine/dioxane.
One method for synthesizing esters, thioesters and amides of substituted 2-thioxo-2H-1-benzopyran-3-carboxylic acids is as follows: 
in which Rxe2x80x2 represents R3 defined above and R represents R5, R6, R7 and/or R8 described above.
The ethyl esters of 2-thioxo-2H-1-benzopyran-3-carboxylic acids can be prepared according to the method described in Shishido Tadao and Okada Hisashi, Jpn. Kokai Tokkyo Koho JP 02,172,916. The subsequent steps are based on the methods described in L. Pochet et al., J. Med. Chem. 1996, 39: 2579-2585 and in the examples of the present patent application.
One method for synthesizing esters, thioesters and amides of substituted 2-thioxo-2H-1-benzopyran-3-carbothioic acids is as follows. 
in which Rxe2x80x3 represents R3 defined above and R represents R5, R6, R7 and/or R8 described above.
The o-ethyl esters of 2-thioxo-2H-1-benzopyran-3-carbothioic acids can be prepared according to the method described in A. Avetisyan et al., Khim. Geterosilk. Soedin., 1996, 7:909-912. The subsequent steps are based on the methods described in L. Pochet et al., J. Med. Chem. 1996, 39: 2579-2585 and in the examples of the present patent application.
The coumarin derivatives of the invention can be used in the preparation of pharmaceutical compositions.
These pharmaceutical compositions can be in the form of solutions, suspensions, powders or soluble granules, syrups or elixirs, ear drops, nose drops or eye drops, tablets, gelatin capsules, aerosols, ointments, transcutaneous or suppository applications, in dosed presentations containing non-toxic supports, adjuvants and excipients. The injections can be, for example, intravenous, intramuscular, subcutaneous, intradermal, intrasternal, intraperitoneal or intra-articular. It is also possible to use infusion or instillation methods (for example intratracheal methods).
In order to target the pulmonary tissue more particularly, solutions containing albumin microspheres to which the coumarin derivatives are bound covalently can be produced.
The preparations for oral use can comprise one or more sweeteners, dyes, flavorings and preserving agents. The tablets contain the coumarin-based active molecule according to the invention mixed with non-toxic pharmaceutically acceptable excipients. Examples of excipients are inert diluents, such as calcium or sodium carbonate, calcium or sodium phosphate and lactose; granulating and disintegrating agents, for example corn starch; binders, for example gelatin, starch and gum arabic; and lubricants, for example talc or magnesium stearate. The tablets can be coated or uncoated (for example using glyceryl monostearate or distearate) in order to delay the disintegration and absorption.
The preparation can be contained in a solid gelatin capsule containing the active molecule mixed with an inert solid (for example calcium carbonate or phosphate, or kaolin), or in a soft gelatin capsule. in which the coumarin derivative is mixed with water or fatty substances (for example liquid paraffin, olive oil or groundnut oil).
Aerosols of three types in particular can be envisaged: (a) aqueous aerosols (administered using atomizers) for which better solubilization of the coumarin derivative can be obtained by adding a co-solvent or formation of micelles; (b) pressurized aerosols whose vector gases are, for example, chloro- or fluorohydrocarbons of various formulae (or a substitute product) in which the coumarin derivative may be dissolved or in suspension; (c) aerosols in powder form with the coumarin derivative as fine particles, for example in a gelatin capsule.
Aqueous suspensions containing the coumarin derivative and the appropriate excipients can be produced, optionally with one or more preserving agents (for example ethyl p-hydroxybenzoate), dyes, sweeteners and flavorings. Among the excipients, mention may be made of suspending agents (for example methylcellulose and gum arabic), dispersants and wetting agents such as natural phosphatides (for example lecithin) or products for condensing ethylene oxide with various partially esterified fatty acids or aliphatic alcohols. Oily suspensions of the active molecule can be prepared using a plant oil (for example olive oil, groundnut oil, sesame oil, coconut oil or soybean oil) or a mineral oil (for example liquid paraffin), optionally in the presence of sweeteners and flavorings such as those mentioned above, as well as preserving agents (in particular an antioxidant such as ascorbic acid).
Syrups or elixirs may contain sweeteners (for example sucrose or sorbitol), one or more preserving agents and flavorings. Granules or powders, which may be suspended in water, can be obtained by mixing the coumarin derivative with a wetting agent or dispersant, one or more preserving agents and various excipients. Emulsions of the coumarin derivative in water can be produced using a mineral oil (for example liquid paraffin) or a plant oil (olive oil or groundnut oil) and various emulsifiers, such as natural gums (gum arabic), natural phosphatides (lecithin) and various fatty acids, which may or may not be partially esterified, or condensation products of these partial esters with ethylene oxide. The emulsions can also contain flavorings and sweeteners.
The coumarin derivative according to the invention can also be in the form of aqueous or oily, injectable sterile suspensions using wetting or suspending agents such as those described above. The solvents, diluents or excipients can be, for example, 1,3-butanediol, an isotonic sodium chloride solution, a Ringer solution, water, aqueous solutions of dextrose and similar sugars, ethanol or glycols, etc. Suppositories containing the active principle can be prepared with conventional excipients such as polyethylene glycol or, for example, cocoa butter. For local uses, it is possible to prepare ointments, creams, jellies, suspensions, solutions, etc. containing the active principle. This can be carried out by preparing a solution of the active principle in a solvent which is known to promote transdermal absorption, such as ethanol or dimethyl sulfoxide (DMSO) with or without excipient. Local administration will preferably be carried out by means of a patch of porous reservoir-membrane type or of solid matrix type. Other transdermal administration systems such as those described in U.S. Pat. Nos. 3,742,951, 3,797,494, 3,966,934, 4,031,894 and 3,921,636 are also applicable.
Doses of from 0.01 to 50 mg/kg/day are appropriate. However, the dose for a given patient may depend upon a certain number of factors, such as, for example, the efficacy of the coumarin derivative considered, the age, weight, route and frequency of administration, the dietary regime, medicinal interactions and the seriousness of the complaint.
These compositions may be used in particular for treating a great many pathologies in which an excess of protease is involved.
This is the case in particular for coumarin derivatives which behave like inhibitors of leukocyte elastase and of cathepsin G. They can be used in the treatment of acute or chronic inflammatory processes or the treatment of degenerative processes, irrespective of the organ involved, such as pulmonary emphysema, inflammation of the bronchi, rheumatoid arthritis, infectious arthritis, osteoarthritis, spondylarthritis, rheumatic fever, periodontitis, gingivitis, arteriosclerosis, glomerulonephritis, respiratory distress syndrome, septic shock, Crohn""s disease, gout, pancreatitis, microvascular hemorrhage, mucoviscidosis, lupus erythematosus, psoriasis, respiratory insufficiency, idiopathic pulmonary fibrosis, chronic infections of the respiratory pathways, ischemia re-infusion syndrome and the phenomena of invasion and diffusion of malignant cells and similar diseases.
Thrombin inhibitors can be useful as anticoagulants or antithrombotic agents, in particular in the treatment of stable and unstable angina, diseases of thrombotic origin and/or which give rise to thrombotic complications (for example thrombophlebitis) and in the treatment and prevention of myocardial infarction and venous and arterial thrombosis.
Inhibitors of plasminogen activators or plasmid activators can be used in particular in the treatment of tumoral invasion and metastases, controlling thrombolysis and fertility, in various clotting disorders (deep vein thrombosis, coronary diseases), in various inflammatory processes (rheumatoid arthritis, psoriasis, leprosy, transplant rejection), in cicatrization, liver disorders and various infections.
Inhibitors of mastocyte tryptases and kinases can be used in the treatment of allergic responses and psoriasis.
Inhibition of cysteine proteases (for example cathepsin B) with the coumarin derivatives can lead to applications in tumoral invasion and the metastasic process.
The coumarin-based active principle can also be used in the composition of cosmetic preparations such as creams, ointments, lotions, gels, milks, etc. They may thus be continuous systems (aqueous, oily or solid solutions) or dispersed systems (emulsions or suspensions). In particular, the coumarin derivative may be contained in liposomes. Hylanes (hyaluronane derivatives) and various polymeric systems (polyol prepolymers, microspheric systems, etc.) can also be used as vehicles for the active principle.
Examples of such compositions are:
(Comment: 1000xc2x0 cetomacrogol=polyoxymethylenated cetostearyl alcohol
aqua conservans=0.07% (m/v) methyl p-aminobenzoate (NIPANGINE) 0.03% (m/v) propyl p-aminobenzoate (NIPASOL) in distilled water)
(Comment: cetiol Vxc2x0=decyl oleate)
The anti-elastase action of the coumarin derivatives can also lead to applications in cosmetology, in particular in the field of solar erythema, the topical treatment of inflammation and ageing of the skin. The active principle can be included, for example, in creams, lotions, tonics, body milks, etc.